Genetic and environmental components of interindividual variation in circulating levels of IGF-I, IGF-II, IGFBP-1, and IGFBP-3.

We assessed the magnitude of the genetic component in the variation of circulating levels of insulin-like growth factors I and II (IGF-I and IGF-II), and their binding proteins IGFBP-1 and IGFBP-3 by measuring their serum concentrations in 32 monozygotic and 47 dizygotic adult twin pairs of the same sex. The intrapair correlation for the IGF-I levels was r = 0.41 (P < 0.009) for monozygotic twins and r = 0.12 (P < 0.22) for dizygotic twins. For the IGF-II concentration the intrapair correlations were r = 0.66 (P < 0.0001) for the monozygotic and r = 0.34 (P < 0.01) for the dizygotic twins. No significant intrapair correlation was found for IGFBP-1 levels in either group. The correlations for IGFBP-3 concentration were r = 0.65 (P < 0.0001) and r = 0.23 (P < 0.06) for monozygotic and dizygotic twins, respectively. Women had higher IGF-II levels than men (635+/-175 vs. 522+/-144 microg/liter; P < 0.0001) and IGFBP-3 levels were also higher in women compared with men (5441+/-1018 vs. 4496+/-1084 microg/liter; P < 0.001). The proportion of variance attributable to genetic effects was 38% for the IGF-I concentration, 66% for the IGF-II concentration, and 60% for the IGFBP-3 concentration. No significant heritability was found for the IGFBP-1 concentrations. Our results show that, in adults, there is a substantial genetic contribution responsible for interindividual variation of the circulating levels of IGF-I, IGF-II, and IGFBP-3, but not for the IGFBP-1 levels.

Infant feeding in Finnish children less than 7 yr of age with newly diagnosed IDDM. Childhood Diabetes in Finland Study Group.

OBJECTIVE: We studied associations between the type of feeding in infancy and the incidence of insulin-dependent diabetes mellitus (IDDM). RESEARCH DESIGN AND METHODS: We studied 103 newly diagnosed diabetic children less than 7 yr of age and 103 age- and sex-matched population-based control children in a countrywide study. RESULTS: The risk of IDDM was decreased (P less than 0.05) among children breast-fed for at least 7 mo (odds ratio [OR] 0.45, 95% confidence interval [CI] 0.24-0.85) or exclusively breast-fed for at least 3 (OR 0.33, 95% CI 0.13-0.84) or 4 (OR 0.43, 95% CI 0.22-0.84) mo. Also, children who were greater than or equal to 4 mo old at the time of introduction of supplementary milk feeding had a lower risk of diabetes (OR 0.48, 95% CI 0.26-0.91). CONCLUSIONS: The protective effects of a long duration of breast-feeding and a late introduction of dairy products on the risk of IDDM remained significant after adjusting for the mother's education.

Mapping genes for NIDDM. Design of the Finland-United States Investigation of NIDDM Genetics (FUSION) Study.

OBJECTIVE: To map and identify susceptibility genes for NIDDM and for the intermediate quantitative traits associated with NIDDM. RESEARCH DESIGN AND METHODS: We describe the methodology and sample of the Finland-United States Investigation of NIDDM Genetics (FUSION) study. The whole genome search approach is being applied in studies of several different ethnic groups to locate susceptibility genes for NIDDM. Detailed description of the study materials and designs of such studies are important, particularly when comparing the findings in these studies and when combining different data sets. RESULTS: Using a careful selection strategy, we have ascertained 495 families with confirmed NIDDM in at least two siblings and no history of IDDM among the first-degree relatives. These families were chosen from more than 22,000 NIDDM patients, representative of patients with NIDDM in the Finnish population. In a subset of families, a spouse and offspring were sampled, and they participated in a frequently sampled intravenous glucose tolerance test (FSIGT) analyzed with the Minimal Model. An FSIGT was completed successfully for at least two nondiabetic offspring in 156 families with a confirmed nondiabetic spouse and no history of IDDM in first-degree relatives. CONCLUSIONS: Our work demonstrates the feasibility of collecting a large number of affected sib-pair families with NIDDM to provide data that will enable a whole genome search approach, including linkage analysis.

Increase in incidence of insulin-dependent diabetes mellitus among children in Finland.

BACKGROUND: In Finland, the incidence of insulin-dependent diabetes mellitus (IDDM) in children aged < 15 years is the highest in the world. The aim of this study was to determine the temporal variation in incidence and the age distribution at diagnosis of IDDM. SUBJECTS AND METHODS: Data on incidence of IDDM in Finland nationwide were obtained from two sources: the Central Drug Registry for the years 1965-1986 (6195 IDDM cases) and the prospective IDDM registry for the years 1987-1992 (2062 IDDM cases). The annual incidence rates were calculated per 100,000 population. The increase in incidence from 1965 to 1992 was estimated by fitting the linear regression with the annual incidence data. RESULTS: The overall incidence of IDDM between 1987 and 1992 was 36 per 100,000/year. During 1965-1992 the increase was almost linear. The regression-based change in incidence was 2.8% per year. In the 1970s the increase in incidence was steepest in 5-9 year olds and since the mid-1980s in those < 5 years old at diagnosis. CONCLUSIONS: The incidence of IDDM in Finnish children seems to increase further. During the last decades the increase in incidence has been almost linear with occasional peaks. The age-at-diagnosis of IDDM has been moving towards the younger ages, and differences in incidence between age groups have now almost disappeared among Finnish children aged 1-14 years.

Alpha 1-adrenoceptor antagonist decreases alpha 2-adrenoceptor antagonist-induced high voltage spindle suppression in adult and aged rats.

The present experiments were undertaken to study whether blockade of alpha 1-adrenoceptors would prevent the high-voltage spindle suppressing effect of atipamezole, an alpha 2-adrenoceptor antagonist. In adult rats, an alpha 1-adrenoceptor antagonist, prazosin, increased dose dependently the high voltage spindles in saline and atipamezole-pretreated rats. In addition, in aged rats prazosin blocked the high-voltage spindle suppressing action of atipamezole. Prazosin produced a smaller increase in high-voltage spindle values in aged than in adult rats. According to the present results, alpha 2-adrenoceptor antagonists may suppress high-voltage spindles indirectly by activating alpha 1-adrenoceptors in young and aged rats.

Record-high incidence of Type I (insulin-dependent) diabetes mellitus in Finnish children. The Finnish Childhood Type I Diabetes Registry Group.

AIMS/HYPOTHESIS: In Finland, the incidence of Type I (insulin-dependent) diabetes mellitus in children aged 14 years or under is the highest in the world and the trend in incidence has been increasing. Our aim was to determine the most recent trends in incidence and the age distribution at diagnosis of Type I diabetes. METHODS: Data on the incidence of Type I diabetes in Finland nationwide were obtained from two sources: for the period 1965 to 1986 from the Central Drug Registry of the Social Insurance Institution and for the period 1987 to 1996 from the prospective childhood Type I diabetes registry. The annual incidence was calculated per 100,000 people. The increase and the trend in incidence were estimated by fitting the linear regression model with the annual incidence data. RESULTS: During 1987 to 1993 the incidence of Type I diabetes seemed to be rather stable at 36 per 100,000 per year. The incidence has continued to increase thereafter and reached 45 per 100,000 per year in 1996. The analysis of the long-term trend in incidence between 1965 and 1996 showed an absolute incidence increase of 0.67 per year on average being 3.4 % compared with the incidence in 1965. The increase from 1987 to 1996 was highest in very young children 1-4 years old at diagnosis. CONCLUSION/INTERPRETATION: The high incidence of Type I diabetes in Finnish children has thus far not levelled off but is increasing further. If the trend continues, the predicted incidence in Finland will be approximately 50 per 100,000 per year in the year 2010.

Maternal vitamin levels during pregnancies producing infants with neural tube defects.

Women at very high risk for having a child with a neural tube defect (NTD) because they had previously delivered affected children significantly reduced their recurrence rate by taking folate supplements before conception. To clarify how these results might apply to a lower-risk general obstetric population, we measured folate, vitamin B12, and retinol levels in maternal serum drawn early in 89 pregnancies resulting in NTD offspring and 178 control pregnancies identified from the Finnish Registry of Congenital Malformations. In 86.5% of the subjects, specimens were collected within 8 weeks after neural tube closure. In the NTD case mothers the mean (+/- SD) levels were not significantly lower than in control mothers: folate, 4.13 +/- 2.36 versus 4.28 +/- 2.52 ng/ml; vitamin B12, 482.8 +/- 161.1 versus 520.3 +/- 191.9 pg/ml; and retinol, 51.2 +/- 17.0 versus 50.5 +/- 16.9 micrograms/dl. After adjustment for age of the specimen, gestational age at which the specimen was drawn, maternal age, and maternal employment status, the odds ratios for being a case mother were 1.00 (95% confidence interval (CI) 0.91 to 1.10) for folate, 1.05 (95% CI 0.92 to 1.19) for vitamin B12, and 0.99 (95% CI 0.88 to 1.10) for retinol. Excluding NTD cases with known or suspected causes unrelated to vitamins, restricting the analyses to interviewed subjects, and excluding subjects whose specimens were collected after 15 gestational weeks confirmed that NTD case and control vitamin levels did not differ significantly. This population-based investigation in a low rate area demonstrated no relationship between maternal serum folate, vitamin B12, or retinol levels during pregnancy and the risk of NTDs.

Antibodies to glutamic acid decarboxylase as predictors of insulin-dependent diabetes mellitus before clinical onset of disease.

We have done a study designed to ascertain the effectiveness of measuring antibodies to glutamic acid decarboxylase (anti-GAD) in predicting insulin-dependent diabetes mellitus (IDDM). Anti-GAD was measured in prediabetic sera from 151 women aged 20-39 years with newly diagnosed diabetes mellitus who had been identified through a nationwide diabetes register. Multiple serum samples had been collected from these women up to 10 years before the clinical onset of diabetes during their earlier pregnancies. Anti-GAD was measured with a radioimmunoprecipitation assay. Anti-GAD was detected in 82% of 28 women with IDDM, in 36% of 11 women with non-insulin-dependent diabetes mellitus, and in 5% of 112 women with gestational diabetes mellitus. In a random sample of 100 non-diabetic young Finnish women, none had anti-GAD. The sensitivity of the anti-GAD assay for predicting IDDM was 82.1% and the specificity was 100%. The longest time of anti-GAD positivity before clinical onset of IDDM was 10 years. Once positive, anti-GAD levels remained stable and no patients became negative after a positive test during the prediabetic period. Anti-GAD is a valuable early predictive marker and is associated with a very high risk for development of IDDM.